6 T cell development An estimated 98% of all thymocytes do not matureThey die by apoptosis within the thymus because:Non productive TCR-gene rearrangementthymic selection.Double-positive thymocytes that express the TCR-CD3 complex and survive thymic selection develop into immature single-positive CD4 thymocytes or single-positive CD8 thymocytes.

7 Selection Ensures MHC Restriction and Non-Self RecognitionPositive selection takes place in the cortical region of the thymus and involves the interaction of immature thymocytes with cortical epithelial cellsPositive selectionNegative selection

8 Thymic SelectionRandom gene rearrangement within TCR germ-line DNA combined with junctional diversity can generate an enormous TCR repertoire (> 1015 for the αβ receptor and 1018 for γδ receptor).TCR has no inherent affinity for foreign antigen plus a self-MHC molecule; they theoretically should be capable of recognizing soluble antigen (either foreign or self), self-MHC molecules or antigen plus a nonself-MHC molecule.

10 Positive SelectionTakes place in the cortical region of the thymus and involves the interaction of immature thymocytes with cortical epithelial cellsThere is evidence that the TCR on thymocytes tend to cluster with MHC molecules on the cortical cells at sites of cell-cell contact.Some researchers have suggested that these interactions allow the immature thymocytes to receive a protective signal that prevents them from undergoing cell deathWhereas no binding with the MCH on thymic epithelial cells the thymocyte do not receive the protective signal and hence undergo apoptosis.

11 Positive SelectionExpression of the RAG-1, RAG-2, and TdT proteins required for gene rearrangement and modificationEach of the immature thymocytes in a clone expressing a given chain have an opportunity to rearrange different TCR -chain genes, and the resulting TCRs are then selected for self-MHC recognition.Only those cells whose TCR heterodimer recognizes a self-MHC molecule are selected for survival.The presence of more than one combination of TCR chains among members of the clone is important because it increases the possibility that some members will “pass” the test for positive selection.Any cell that manages to rearrange an chain that allows the resulting TCR to recognize self-MHC will be spared; all members of the clone that fail to do so will die by apoptosis within 3 to 4 days.

17 Two Theories to Explain Positive and Negative SelectionAvidity theory - differences in the strength of the signals received by thymocytes undergoing positive and negative selection determine the outcome, with signal strength dictated by the avidity of the TCR-MHC-peptide interaction.Differential-signaling hypothesis holds that the outcomes of selection are dictated by different signals, rather than different strengths of the same signal.